p32/OPA1 axis-mediated mitochondrial dynamics contributes to cisplatin resistance in non-small cell lung cancer  

作　　者：Chun-Xia Yu Zhe-Qing Peng Tao Wang Xin-Hui Qu Ping Yang Shao-Rong Huang Li-Ping Jiang Fang-Fang Tou Xiao-Jian Han 

机构地区：[1]Institute of Geriatrics,Jiangxi Provincial People’s Hospital,The First Affiliated Hospital of Nanchang Medical College,Nanchang 330006,China [2]Department of Pharmacology,School of Pharmaceutical Science,Nanchang University,Nanchang 330006,China [3]The Second Department of Neurology,Jiangxi Provincial People’s Hospital,the First Affiliated Hospital of Nanchang Medical College,Nanchang 330006,China [4]Department of Oncology,Jiangxi Provincial People’s Hospital,The First Affiliated Hospital of Nanchang Medical College,Nanchang 330006,China

出　　处：《Acta Biochimica et Biophysica Sinica》2024年第1期34-43,共10页生物化学与生物物理学报（英文版）

基　　金：This work was supported by the grants from the National Natural Science Foundation of China(No.82060177);the Key Science and Technology Innovation Project of Jiangxi Provincial Health Commission(No.2023ZD001);the Research Fund for Jiangxi Geriatric Clinical Medical Research Center(No.2020BCG74003);the Jiangxi Province Natural Science Foundation(No.20224ACB206014);the Key Projects from Department of Education of Jiangxi Province(No.GJJ218902).

摘　　要：Cisplatin resistance is a major obstacle in the treatment of non-small cell lung cancer(NSCLC).p32 and OPA1 are the key regulators of mitochondrial morphology and function.This study aims to investigate the role of the p32/OPA1 axis in cisplatin resistance in NSCLC and its underlying mechanism.The levels of p32 protein and mitochondrial fusion protein OPA1 are higher in cisplatin-resistant A549/DDP cells than in cisplatin-sensitive A549 cells,which facilitates mitochondrial fusion in A549/DDP cells.In addition,the expression of p32 and OPA1 protein is also upregulated in A549 cells during the development of cisplatin resistance.Moreover,p32 knockdown effectively downregulates the expression of OPA1,stimulates mitochondrial fission,decreases ATP generation and sensitizes A549/DDP cells to cisplatin-induced apoptosis.Furthermore,metformin significantly downregulates the expres-sions of p32 and OPA1 and induces mitochondrial fission and a decrease in ATP level in A549/DDP cells.The co-administration of metformin and cisplatin shows a significantly greater decrease in A549/DDP cell viability than cisplatin treatment alone.Moreover,D-erythro-Sphingosine,a potent p32 kinase activator,counteracts the met-formin-induced downregulation of OPA1 and mitochondrial fission in A549/DDP cells.Taken together,these find-ings indicate that p32/OPA1 axis-mediated mitochondrial dynamics contributes to the acquired cisplatin resistance in NSCLC and that metformin resensitizes NSCLC to cisplatin,suggesting that targeting p32 and mitochondrial dynamics is an effective strategy for the prevention of cisplatin resistance.

关 键 词：p32 OPA1 mitochondrial dynamics cisplatin resistance METFORMIN non-small cell lung cancer 

分 类 号：Q244[生物学—细胞生物学] R73[医药卫生—肿瘤]